Liver cancer especially affects oriental countries, including Korea at a high incidence and mortality rate. The liver cancer can be treated by surgical operation in an early stage, when metastasis of cancer cells has not occurred and their size is small. However, as the disease is progressed, the treatment by the surgical operation becomes ineffective. In this case, hepatic arterial embolization is generally used.
Normal liver tissue is supplied with blood and oxygen through both portal veins and arteries, particularly, for the blood the portal veins and arteries being responsible for 75% and 25%, respectively, of the total supply, and for the oxygen the portal veins and arteries being responsible for 50% and 50%, respectively, of the total supply. However, as for a cancerous tissue of the liver, the portal veins take 90% in supplying blood. Based on this fact, if embolic material embolizing to capillary vessel is injected to the hepatic artery of a liver cancer patient, the material is migrated mainly to the liver cancer tissue, causing embolization thereto. One example of the embolic materials is lipiodol.
Lipiodol is a lipid-soluble contrast medium obtained by iodination and esterification of poppy seed oil. Lipiodol has been employed as a contrast medium for imaging lymph nodes. It is easily able to cause capillary embolism due to 38 weight % iodine and high viscosity at room temperature. Therefore, injection of lipiodol to the hepatic artery of a patient with liver cancer results in lipiodol being concentrated into the liver cancer tissue. Using, such information, there were several attempts to treat liver cancer by injecting anticancer agent-assembled lipiodol to the liver cancer tissue.
A method by which lipiodol is labeled with a radioisotope and administered via a hepatic artery to treat liver cancer had been used. It was reported that when administered to patients with liver cancer, 131I-labelled lipiodol is accumulated in liver cancer tissue (M. Nakajo et al., Biodistribution and in vivo kinetics of iodine-131 lipiodol infused via the hepatic artery of patients with hepatic cancer, J. Nucl. Med., 29: 1066–1077, 1988). And, distribution in vivo of 90Y-labelled lipiodol was studied (S-J Wang et al., Preparation and biodistribution of yttrium-90 lipiodol in rats following hepatic arterial injection, Eur. J. Necl. Med., 22: 233–236, 1995). However, there are disadvantages in that I-131 is an isotope not suitable for the treatment, and Y-90 is costly and hard to be imaged, limiting the use thereof. Articles were published to report Re-188 labeling to overcome the above disadvantages (S-J Wang et al., Radiolabelling of lipiodol with generator-produced 188Re for hepatic tumor therapy, Appl. Radiat. Isot., 47: 267–271., 1996; S-J Wang et al., Biodistribution of rhenium-188 lipiodol infused via the hepatic artery of rats with hepatic tumors, Eur. J. Nucl. Med., 23:13–17, 1996). However, the methods presented by these articles need improvement since the labeling method is complicated and the labeling efficiency and its stability are low.
To improve the labeling method, diaminedithiol derivatives with alkyl chain have been developed (T W Jackson et al., Rhenium diamino dithiol complexes. III Lipophilic ligands for endotherapeutic radiopharmaceuticals. Aust. J. Chem. 53:983–987). They synthesized diaminedithiol derivatives with long alkyl chain of C1–C14 and labeled them with radiorhenium. What they found was that only diaminedithiol derivatives with alkyl chain of C1–C10 showed enough stability for treatment of liver cancer. They found that diaminedithiol derivatives with alkyl chain longer than C10 were not stable. Actually, they reported that the yield of complexing rhenium and diaminedithiol containing C10 alkyl chain was so poor that they failed to get enough amount of complex for analysis. It would have been even more difficult for them to obtain rhenium complex with diaminedithiol containing longer alkyl chain in their experiment. That is why they gave up diaminedithiol containing alkyl chain longer than C10. They claimed diaminedithiol derivatives with alkyl chain of C1–C10 for treatment of liver cancer in U.S. Pat. No. 5,496,533. However in our experiment, diaminedithiol containing alkyl chain longer than C10 could make stable lipophilic complex with 183Re. Furthermore, we found that diaminedithiol derivatives with alkyl chain shorter than C13, which includes the compounds in U.S. Pat. No. 5,496.533, were not lipophilic enough to be retained in the tissue, which would result in rapid clearance from cancer tissue. We have proved that diaminedithiol derivatives should have alkyl chain longer than C14, and that is our major claim in this patent.
Meanwhile, diaminedithiol has a structure represented in Formula 1 below. It was synthesized and known to make stable lipophilic complex with technetium or rhenium (H F Kung, et al. Synthesis and biodistribution of neutral lipid-soluble Tc-99 m complexes that cross the blood-brain barrier. J. Nucl. Med. 25:326–332, 1984). Davison et al described a variety of complexes of substituted anionic diaminedithiol with Tc-99 m as an agent for imaging kidney, which was published on Mar. 27, 1985 in Europe Pat. Appln. No. 135,160.

wherein, R1 to R12 are independently hydrogen, alkyl having C1 to C3, or —COOR (in which R is —CH3, —C2H5 or —C3H7); provided that among substituents R1 to R12, only R3, R5, and R7 to R10 may be —COOR.
A kit comprising a neutral lipid-soluble ester-substituted is diaminedithiol is disclosed in Korean Pat. Laid-open No. 92-2107. According to the reference, using a method by which thiazolidine is dimerized via reduction to prepare a N,N′-1,2-ethylenebis-L-cysteine derivative and ester, thereof (Blondeau et al., Can. J. chem., 45:46, 1967). ligand is synthesized and labeled with Tc-99 m to form a neutral lipid-soluble complex, being directed to imaging blood flow in the brain.
In U.S. Pat. No. 5,980,860 published on Nov. 9, 1999, it is described that diaminedithiol derivatives are synthesized by introducing tropane group to use as a radiopharmaceuticals for imaging dopamine transporter.